Change of metabolism in malignancy

Cancer cells can modify their metabolism to proliferate and to adapt to stressful environmental conditions. In many cases, cancer cells adapt to adenosine triphosphate (ATP) production through glycolysis versus its generation through oxidative phosphorylation. This shift is known as the Warburg effect.

Pyruvate is an important metabolite that plays a role in switching between glycolysis in the cytosol and oxidative phosphorylation in mitochondria. The objectives of the EU-funded 'Involvement of mitochondrial pyruvate carrier in tumorogenesis' (IMPACT) project have been to investigate the functional properties of the mitochondrial pyruvate carrier (MPC) in normal and cancer cells.

MPC imports pyruvate inside mitochondrion if it is not reduced into lactate by lactate dehydrogenase. Researchers hypothesised that abnormal activity of the MPC in cancer cells causes, at least in part, the Warburg effect.

Researchers genetically engineered a biosensor that was based on bioluminescence resonance energy transfer (BRET) to monitor activity of the MPC. After obtaining proof-of-concept for the biosensor, they determined MPC activity in a number of normal and cancer cells. The generated cell lines stably expressed the MPC BRET sensor. These experiments allowed validating the functionality of the BRET sensor.

IMPACT members observed an increase in MPC activity in both normal and cancer cells in response to pyruvate. These types of changes were not observed in cancer cells when glucose was provided as the only carbon source. The results suggest that changes in pathways upstream of pyruvate import mostly resulted in the Warburg effect observed in different tumours.

The novel BRET assay allows identification of the mechanisms that prevent pyruvate from being imported into mitochondria. Proteins involved in this process might present new therapeutic targets for cancer treatment.